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VelociGene coupled with VelocImmune yield Dll4 as a Tumor Angiogenesis Target
Author(s) -
Gale Nicholas William
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.524.7
Subject(s) - blockade , angiogenesis , cancer research , monoclonal antibody , medicine , neovascularization , regulator , vegf receptors , antibody , receptor , immunology , biology , biochemistry , gene
Clinically blocking VEGF can have efficacy in cancer and in vascular eye diseases. However, data suggests that in some cases tumor growth and angiogenesis can proceed in the face of potent VEGF blockade. To define new targets in the field of angiogenesis we exploited our mouse genetics approaches, VelociGene and VelociMouse. One new target, termed Delta‐like ligand 4 (Dll4), is induced by VEGF as a negative feedback regulator. Knockout or blockade of this feedback system during vascular development or in tumor settings results in uncontrolled excessive angiogenesis. Paradoxically, in tumors, this excessive angiogenesis results in suppression of tumor growth, apparently because the excess vasculature cannot support tumor perfusion. Dll4‐blockade is effective in several tumor models resistant to anti‐VEGF therapies and Dll4‐blockade can also be effectively combined with anti‐VEGF therapies. We have used our VelocImmune platform, a new mouse system for rapidly and efficiently generating fully human monoclonal antibodies against targets of interest, to generate high‐affinity fully human antibody therapeutic candidates that block Dll4.